This invention relates to 11xcex2-long-chain-substituted estratrienes of general formula I 
in which
R3 means a hydrogen atom, a hydrocarbon radical with up to 8 carbon atoms or a radical of partial formula R3xe2x80x2xe2x80x94C(O)xe2x80x94, in which R3xe2x80x2 means a hydrogen atom or a hydrocarbon radical with up to 8 carbon atoms or a phenyl radical,
R11 means a radical of formula xe2x80x94Axe2x80x94Bxe2x80x94Zxe2x80x94R20, in which
A stands for a direct bond, and
B stands for a straight-chain or branched-chain alkylene, alkenylene or alkinylene group with 4, 5 or 6 carbon atoms, or
A stands for a phenylene radical, and
B stands for a methylene, ethylene, propylene or trimethylene group, or
A stands for a phenylenoxy radical, whereby the latter is bonded via a carbon atom to the 11-carbon atom of the steroid, and
B stands for an ethylene group, and
Z stands for xe2x80x94NR21xe2x80x94 and R21 stands for a C1-C3 alkyl group,
whereby R20 means
a hydrogen atom,
a straight-chain or branched-chain alkyl, alkenyl or alkinyl group with up to 10 carbon atoms, whereby if A is a direct bond, R20 and R21 do not both simultaneously mean methyl, however, and, if A is a phenylenoxy radical, R20 and R21 do not both simultaneously mean methyl or ethyl in each case, and if A is a phenylenoxy radical and B means an ethylene group, OR17b should not be a hydroxy group and R17a should not be a C1-4 alkyl group, and R3 should not be a hydrogen atom,
or one of groupings
xe2x80x94Dxe2x80x94CnF2n+1, whereby D is a straight-chain or branched-chain alkylene, alkenylene or alkinylene group with up to 8 carbon atoms and n is an integer from 1 to 8, D-aryl, whereby D has the already indicated meaning, and aryl stands for a phenyl, 1- or 2-naphthyl radical or a heteroaryl radical that is optionally substituted in one or two places,
xe2x80x94Lxe2x80x94CHxe2x95x90CFxe2x80x94CpF2p+1, whereby L is a straight-chain or branched-chain alkylene, alkenylene or alkinylene group with up to 7 carbon atoms and p is an integer from 1 to 7,
whereby in the three cases above in D or L, a methylene group can be replaced by a sulfur atom, a sulfone group or a sulfoxide group,
xe2x80x94Dxe2x80x94Oxe2x80x94(CH2)q-aryl, whereby D and aryl have the already indicated meanings, and q is 0, 1, 2 or 3,
xe2x80x94Dxe2x80x94Oxe2x80x94(CH2)rxe2x80x94CnF2n+1, whereby D and n have the already indicated meanings, and r stands for an integer from 1 to 5,
whereby in addition in all relevant cases above, R21 together with D with the inclusion of the nitrogen atom can then form a pyrrolidine ring that is substituted in 2- or 3-position, or
if A is a direct bond or a phenylene radical, R20 and R21 with the nitrogen atom to which they are bonded form a saturated or unsaturated heterocyclic compound with 5 or 6 chain links, which optionally contains one or two additional heteroatoms, selected from nitrogen, oxygen and sulfur, and optionally is substituted,
whereby if A is a phenylene radical and B is a trimethylene radical, R21 and R20 do not form a methyl or ethyl group, or, together with the nitrogen atom to which they are bonded, do not form a pyrrolidine or and
R17axcex1in xcex1- or xcex2-position means a hydrogen atom, a C1-5 alkyl, a C2-5 alkenyl or a C2-5 alkinyl group or a trifluoromethyl group, or together with the radical OR17b means a keto-oxygen atom, and
R17b means a hydrogen atom or a radical of partial formula R17xe2x80x2xe2x80x94C(O)xe2x80x94, in which R17xe2x80x2 means a hydrogen atom or a hydrocarbon radical with up to 8 carbon atoms.
As R3, the substituted estratrienes according to the invention preferably have a hydrogen atom. The hydroxy group, however, can also be etherified with a straight-chain or branched-chain, saturated or unsaturated hydrocarbon radical with up to 8 carbon atoms, such as, e.g., a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl or octyl radical or esterified with an acyl radical R3xe2x80x2xe2x80x94C(O)xe2x80x94, in which R3xe2x80x2 is a hydrogen atom or a hydrocarbon radical with up to 8 carbon atoms or a phenyl radical.
A hydrogen atom or a radical of partial formula R17xe2x80x2xe2x80x94C(O)xe2x80x94 can stand for substituents R17b, in which R17xe2x80x2 is a hydrogen atom or a hydrocarbon radical with up to 8 carbon atoms. A hydrogen atom is preferred for R17b. The hydrocarbon radical can have the meaning of, for example, a methyl, ethyl, propyl, isopropyl; butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, heptyl, hexyl or octyl radical. In addition, the substituent xe2x80x94OR17b can be in xcex1- or xcex2-position. The xcex2-position is preferred.
R17b can mean a hydrogen atom, a straight-chain or branched C1-5 alkyl radical, such as, for example, a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl radical, a straight-chain or branched C2-5 alkenyl radical, such as, for example, an ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-ethyl-ethenyl, 2-ethylethenyl, 1-methyl(1-propenyl), 1-methyl(2-propenyl) radical, or a straight-chain or branched C2-5 alkinyl radical, such as, for example, an ethinyl, 1-propinyl, 2-propinyl, 1-butinyl, 2-butinyl, 3-butinyl, 3-methyl (1-butinyl)-, 1-methyl (3-butinyl) radical and a trifluoromethyl radical.
R17b preferably means a hydrogen atom, a C2-3 alkenyl radical, a C2-3 alkinyl radical or a trifluoromethyl group.
R17a especially preferably means a hydrogen atom, a methyl group, an ethenyl radical, an ethinyl radical or a trifluoromethyl group.
In addition, the radical R17a can be in xcex1- or xcex2-position. The xcex1-position is preferred for R17a.
Another meaning for R17b together with OR17a is a keto-oxygen atom. This meaning is to be preferred before any other substitution in 17-position.
In the compounds of general formula I according to the invention, A stands for a direct bond, a phenylene or phenylenoxy radical, whereby the latter is connected via one of its carbon atoms to carbon atom 11 of the steroid skeleton.
An aryl radical that optionally can be substituted is a phenyl, 1- or 2-naphthyl radical in terms of this invention; the phenyl radical is preferred. Unless expressly indicated otherwise, aryl also always includes a heteroaryl radical. Examples of a heteroaryl radical are the 2-, 3- or 4-pyridinyl, the 2- or 3-furyl, the 2- or 3-thienyl, the 2- or 3-pyrrolyl, the 2-, 4- or 5-imidazolyl, the pyrazinyl, the 2-, 4- or 5-pyrimidinyl or the 3- or 4-pyridazinyl radical.
If R20 and R21 with the nitrogen atom, to which they are bonded, contain a saturated or unsaturated heterocycle with 5 or 6 chain links, which optionally contains one or two additional heteroatoms that are selected from nitrogen, oxygen and sulfur, this is especially a pyrrolidine, piperidine, morpholine or piperazine ring
As substituents for the aryl, heteroaryl, aralkyl and heteroarylalkyl radicals, for example, a methyl-, ethyl-, propyl-, trifluoromethyl-, pentafluoroethyl-, trifluoromethylthio-, methoxy-, ethoxy-, nitro-, cyano-, halogen-(fluorine, chlorine, bromine, iodine), hydroxy-, amino-, mono(C1-8 alkyl)- or di(C1-8 alkyl)amino, whereby both alkyl groups are identical or different, di(aralkyl)amino, whereby both aralkyl groups are identical or different (for aralkyl, see above at R20 and R31) or the 1-methoxyacetylamino radical can be mentioned.
The sulfur atom in the side chain can be present as a single sulfur bridge (sulfide), as sulfone or sulfoxide.
As specific side chains,
xe2x80x94(CH2)5N(CH3)xe2x80x94(CH2)3xe2x80x94Sxe2x80x94(CH2)3C2F5 
xe2x80x94(CH2)5NHxe2x80x94(CH2)3xe2x80x94Sxe2x80x94(CH2)3C2F5 
xe2x80x94(CH2)5N(CH3)xe2x80x94(CH2)3xe2x80x94Sxe2x80x94CH2-2-Pyridyl
xe2x80x94(CH2)5N(CH3)xe2x80x94(CH2)3xe2x80x94SOxe2x80x94CH2-2-Pyridyl
xe2x80x94(CH2)5N(CH3)xe2x80x94(CH2)3xe2x80x94Sxe2x80x94CH2-p-CF3-Phenyl
xe2x80x94(CH2)5N(CH3)xe2x80x94(CH2)3xe2x80x94SOxe2x80x94CH2-p-CF3-Phenyl
xe2x80x94(CH2)5-[2-Pyrrolidin-1-yl]xe2x80x94CH2xe2x80x94S-p-CF3-Phenyl
xe2x80x94(CH2)5-[2-Pyrrolidin-1-yl]xe2x80x94CH2xe2x80x94SO-p-CF3-Phenyl
p-Phenylen-(CH2)2xe2x80x94N(CH3)xe2x80x94(CH2)3xe2x80x94Sxe2x80x94(CH2)3C2F5 
p-Phenylen-(CH2)2xe2x80x94N(CH3)xe2x80x94(CH2)3xe2x80x94SOxe2x80x94(CH2)3C2F5 
p-Phenylen-(CH2)2xe2x80x94N(CH3)xe2x80x94(CH2)3xe2x80x94Sxe2x80x94CH2-2-Pyridyl
p-Phenylen-(CH2)2xe2x80x94N(CH3)xe2x80x94(CH2)3xe2x80x94SOxe2x80x94CH2xe2x80x942-Pyridyl
p-Phenylen-(CH2)2xe2x80x94N(CH3)xe2x80x94(CH2)3xe2x80x94Sxe2x80x94CH2-p-CF3-Phenyl
p-Phenylen-(CH2)2xe2x80x94N(CH3)xe2x80x94(CH2)3xe2x80x94SOxe2x80x94CH2-p-CF3-Phenyl
xe2x80x94(CH2)5N(CH3)(CH2)3C2F5 
xe2x80x94(CH2)5N(CH3)(CH2)6C2F5 
xe2x80x94(CH2)5N(CH3)(CH2)7C2F5 
xe2x80x94(CH2)5N(CH3)(CH2)8C2F5 
xe2x80x94(CH2)6N(CH3)(CH2)6C2F5 
xe2x80x94(CH2)6N(CH3)(CH2)7C2F5 
xe2x80x94(CH2)6N(CH3)(CH2)8C2F5 
xe2x80x94(CH2)5N(CH3)(CH2)2C4F9 
xe2x80x94(CH2)5N(CH3)(CH2)3C6F13 
xe2x80x94(CH2)5N(CH3)(CH2)3C8F17 
xe2x80x94(CH2)5N(CH3)(CH2)6C4F9 
xe2x80x94(CH2)5N(CH3)(CH2)6C6F13 
xe2x80x94(CH2)5N(CH3)(CH2)6C8F17 
xe2x80x94(CH2)5N(CH3)H
xe2x80x94(CH2)5N(CH3)(CH2)9H
xe2x80x94(CH2)5N(CH3)CH2CHxe2x95x90CFxe2x80x94C2F5 
xe2x80x94(CH2)5N(CH3)CH2CHxe2x95x90CFxe2x80x94C3F7 
xe2x80x94(CH2)5N(CH3)CH2CHxe2x95x90CFxe2x80x94C5F11 
xe2x80x94(CH2)5N(CH3)CH2CHxe2x95x90CFxe2x80x94C7F15 
xe2x80x94(CH2)5-1-Pyrrolidinyl
xe2x80x94(CH2)5N(CH3)(CH2)3OPhenyl
xe2x80x94(CH2)5N(CH3)(CH2)3OBenzyl
xe2x80x94(CH2)5N(CH3)(CH2)3O(CH2)3C2F5 
xe2x80x94(CH2)5N(CH3)(CH2)3CH(CH3)2 
xe2x80x94(CH2)5N(CH3)(CH2)3-Pyridyl
xe2x80x94(CH2)5N(CH3)(CH2)3-Phenyl
xe2x80x94(CH2)5N(CH3)(CH2)2-p-Tolyl
xe2x80x94(CH2)5N(CH3)(CH2)2-p-Ethoxyphenyl
xe2x80x94(CH2)5N(CH3)(CH2)3-p-Tolylxe2x88x92
xe2x80x94(CH2)5N(CH3)(CH2)3-p-Chlorphenyl
xe2x80x94(CH2)5N(CH3)(CH2)3xe2x80x94Oxe2x80x94CH2-Phenyl
xe2x80x94(CH2)5N(CH3)(CH2)2xe2x80x94O-p-Br-Phenyl
xe2x80x94(CH2)5N(CH3)(CH2)2xe2x80x94O-p-CF3-Phenyl can be mentioned.
[Key:]
xe2x80x94(CH2)5-[2-Pyrrolidin-1-yl]- . . . =(CH2)5-[2-pyrrolidine-1-yl]- . . . p-Phenylen- . . . =p-phenylene- . . .
This invention relates to the following compounds, i.a.:
11xcex2-[5-(Methyl(3-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]-propyl}amino)pentyl]estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-(5-{3-[(4;4,5,5,5-pentafluoropentyl)sulfanyl]propyl-amino}pentyl)estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-[5-(methyl{3-[(2-pyridylmethyl)sulfanyl]propyl}-amino)pentyl]estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-[5-(methyl{3-[(2-pyridylmethyl)sulfinyl]propyl}-amino)pentyl]estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-[5-(methyl{3-[4-(trifluoromethyl)benzylsulfanyl]-propyl}amino)pentyl]estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-[5-(methyl{3-[4 -(trifluoromethyl)benzylsulfinyl]-propyl}amino)pentyl]estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[(2S)-2-{[4-(trifluoromethyl)phenyl]sulfanyl-methyl}pyrrolidin-1-yl]pentyl}estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[(2S)-2-{[4-(trifluoromethyl)phenyl]sulfinyl-methyl}pyrrolidin-1-yl]pentyl}estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{4-[2-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulfanyl]-propyl}amino)ethyl]phenyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{4-[2-(methyl{3-[(4,4,5,5,5-pentafluoropentyl)sulfinyl]-propyl}amino)ethyl]phenyl}estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{4-[2-(methyl{3-[(2-pyridylmethyl)sulfanyl]propyl}-amino)ethyl]phenyl}estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{4-[2-(methyl{3-[(2-pyridylmethyl)sulfinyl]propyl}-amino)ethyl]phenyl}estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{4-[2-(methyl{3-[4-(trifluoromethyl)benzylsulfanyl]-propyl}amino)ethyl]phenyl}estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{4-[2-(methyl{3-[4-(trifluoromethyl)benzylsulfinyl]-propyl}amino)ethyl]phenyl}estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[methyl-(8,8,9,9,9-pentafluoro-nonyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5[methyl-nonyl-amino]-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[methyl-(9,9,10,10,10-pentafluoro-decyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{6-[methyl-(8,8,9,9,9-pentafluoro-nonyl)amino]-hexyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{6-[methyl-(9,9,10,10,10-pentafluoro-decyl)-amino]-hexyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-(5-(methyl-amino)-pentyl)-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-(5-pyrrolidin-1-yl-pentyl)-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[methyl-(4,4,5,5,5-pentafluoro-pentyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[methyl-(4,4,5,5,6,6,7,7,8,8,9,9,9-tridecafluoro-nonyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[(4,4,5,5,6,6,7,7,8,8,9,9,10,10,11,11,11-heptadecafluoro-undecyl)-methyl-amino]-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[methyl-(3,3,4,4,5,5,6,6,6-nonafluoro-hexyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[methyl-(7,7,8,8,8-pentafluoro-octyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{6-[methyl-(7,7,8,8,8-pentafluoro-octyl)-amino]-hexyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[methyl-(7,7,8,8,9,9,10,10,10-nonafluoro-decyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[methyl-(7,7,8,8,9,9,10,10,11,11,12,12,12-tridecafluoro-dodecyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[(7,7,8,8,9,9,10,10,11,11,12,12,13,13,14,14,14-heptadecafluoro-tetradecyl)-methyl-amino]-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[(3,4,4,5,5,5-hexafluoro-pent-2-enyl)-methyl-amino]-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[(3,4,4,5,5,6,6,7,7,8,8,8-dodecafluoro-oct-2-enyl)-methyl-amino]-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[(3,4,4,5,5,6,6,7,7,8,8,9,9,10,10,10-hexadecafluoro-dec-2-enyl)-methyl-amino]-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[methyl-(3-phenoxy-propyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[(3-benzyloxy-propyl)-methyl-amino]-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[N-methyl-N-3-(4,4,5,5,5-pentafluoropentyloxy)-propylamino]-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[methyl-(2-p-tolyl-ethyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-(5-{[2-(4-ethoxy-phenyl)-ethyl]-methyl-amino}-pentyl)-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[methyl-(3-phenyl-propyl)-amino)-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[methyl-(3-pyridin-3-yl-propyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[methyl-(3-p-tolyl-propyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-(5-{[3-(4-chloro-phenyl)-propyl]-methyl-amino}-pentyl)-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-(5-{[3-(4-ethoxy-phenyl)-propyl]-methyl-amino}-pentyl)-estra-1,3,5(10)-triene-3,17xcex2-diol
11xcex2-{5-[methyl-(4-methyl-pentyl)-amino]-pentyl}-estra-1,3,5(10)-triene-3,17xcex2-diol
In addition to these compounds of general formula I, this invention also relates to their physiologically compatible addition salts with organic and inorganic acids, pharmaceutical preparations that contain these compounds of general formula I inclusive of the addition salts, as well as their use for the production of pharmaceutical agents.
Inorganic and organic acids, as are known to one skilled in the art for the formation of physiologically compatible salts, are suitable for the formation of acid addition salts. As addition salts with acids, especially hydrochlorides, hydrobromides, acetates, citrates, oxalates, tartrates and methanesulfonates can be cited.
The compounds of general formula I represent compounds with strong antiestrogenic action and with surprising possible oral uses.
The compounds according to the invention are either pure antiestrogens or so-called partial antagonists, i.e., antiestrogens with partial estrogenic action such as tamoxifen or raloxifen. In contrast to the tamoxifen, their agonistic, estrogenic action is expressed in a tissue-selective manner in the case of partial antagonists of general formula I. In particular, the agonistic action occurs in bone, in the cardiovascular system and in the central nervous system. In particular, no action or only slightly agonistic action occurs in the uterus.
Compounds with antiestrogenic properties, i.e., substances with inhibiting actions compared to estrogens, have already been described extensively.
Estratrienes that carry a xcex2-position substituent in 11-position and that also have, i.a., antiestrogenic action, are known from, for example, the following patent applications:
WO 98/28324, EP-A 0 850 647, EP-A 0 629 635, WO 93/13123, EP-A 0 558 416, EP-A 0 471 612, EP-A 0 384 842, EP-B 0 097 572, WO/99 25725.
In addition, the steroid derivatives that are known from EP 0 138 504 B1 can be mentioned. The 7xcex1-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-n-nonyl]-estra-1,3,5(10)-triene-3,17xcex2-diol is currently under clinical development for hormone-dependent tumors (breast cancer).
Pharmaceutical compositions that contain sex steroid inhibitors and that have a steroidal skeleton that has a 7xcex1-side chain in the case of the simultaneous presence of at least one other substituent in 14-, 15- or 16-position are the subject matter of EP-A 0 376 576.
Antiestrogenically active estratrienes that can carry an 11xcex2-fluorine atom and carry an a-position side chain in 7-position, which has an amino group and a sulfur group and that is functionalized in the terminal position, are described in WO 98/07740.
The compounds according to the invention are compounds with stronger antiestrogenic action after peroral administration.
The antiuterus growth test in infant rats, s.c. and p.o. (test on antiestrogenic action in-vivo) confirms the antiestrogenic action of the compounds according to the invention. The test is performed as described below:
In rodents, the uterus reacts to the administration of estrogens with an increase in weight (both proliferation and water retention). This growth can be inhibited in a dose-dependent manner by simultaneous administration of compounds that have an antiestrogenic action.
Animals:
Infant female rats weighing 35-45 g at the beginning of the test, 5-6 animals per dose.
Formulation and Administration of the Substances:
For the p.o. administration, the substances are dissolved in 1 part ethanol (E) and made up with 9 parts peanut oil (Exc3x96).
The young rats just dropped by the mothers are delivered for acclimation one day before the beginning of treatment and immediately supplied with foodxe2x80x94right in the cage. The treatment is then carried out once daily over 3 days in combination with 0.5 xcexcg of estradiol benzoate (EB). EB is always administered subcutaneously (s.c.), while the test substance is administered p.o. (perorally). 24 hours after the last administration, the animals are weighed, killed and the uteri are removed. The moist weight (less contents) is determined from the prepared uteri.
Negative control: Vehicle (E/Ë), 0.2 ml/animal/day
Positive control: 0.5 xcexcg of EB/0.1 ml/animal/day
The average values with standard deviation (X+SD) and the significance of the differences in the control group (EB) in the Dunnett Test (p less than 0.05) are determined for each group from the relative organ weights (mg/100 g of body weight). The calculation of the inhibition (in %) compared to the EB-control is carried out with a program. The relative actions of the test substances are determined by co-variance analysis and regression analysis.
As pure antiestrogens for the purposes of this invention, those compounds of general formula I that show no action or, in the best case, only slightly agonistic action, in the in-vitro test on estrogenic action can be considered.
By means of the method described below, the estrogenic effect of the compounds according to the invention on the bones can be determined. In the case of selectively estrogenically active compounds, protective effects on the bones are observed with comparable dosages, while on the uterus, no stimulation, or in the best case, only slight stimulation, is noted.
Female rats that are three months old are ovariectomized and treated once daily with the test compound immediately after the operation for 28 days. The administration is carried out subcutaneously in castor oil/benzyl benzoate or arachis oil/ethanol. The animals are sacrificed on the day after the last administration, and femurs, tibia as well as the uteri are removed. The uteri are weighed, mounted and worked up for histological studies. The determination of the bone density is carried out ex vivo on prepared long bones via pQCT (Quantitative Computer Tomography). The measurements are made at a distance of 5-7 mm from the ball of the joint at the distal femur or the proximal tibia.
As an alternative, the action on the bones by measuring out the trabecular bone surface area of the secondary spongiosa on histologic preparations of the distal femur or the proximal tibia is noted. The result is expressed as the proportion, in percent, of the trabecular bone surface area to the measured total bone surface area (TB/BV). The bone density that is measured via QCT and the trabecular bone surface area that is determined at the histologic section correlate well with one another. A comparison of the two measurement variables is therefore permissible.
The transition between the pure antiestrogens and the partial agonists, the tissue-selective estrogens, is seamless. Compounds that have a slightly agonistic action can also be used in the indications that are mentioned below for pure antiestrogens:
The compounds according to the invention, especially if they are pure antiestrogens, are suitable for treatment of estrogen-dependent diseases, for example breast cancer (second-line treatment of tamoxifen-resistant breast cancer; for adjuvant treatment of breast cancer instead of tamoxifen), endometrial cancer, prostate cancer, prostatic hyperplasia, anovulatory infertility and melanoma.
In addition, the pure antiestrogens of general formula I can be used as components in the products that are described in EP 346 014 B1, which contain an estrogen and a pure antiestrogen, specifically for simultaneous, sequential or separate use for selective estrogen therapy of peri- or postmenopausal women. The compounds of general formula I, especially if these are pure antiestrogens, can be used together with antigestagens (competitive progesterone antagonists) for the treatment of hormone-dependent tumors (EP 310 542 A).
Other indications in which the compounds of the general formula can be used are male hair loss, diffuse alopecia, alopecia that is caused by chemotherapy as well as hirsutism (Hye-Sun Oh and Robert C. Smart, Proc. Natl. Acad. Sci. USA, 93 (1996) 12525-12530).
In addition, the compounds of general formula I can be used for the production of medications for treating endometriosis and endometrial carcinomas.
The compounds of general formula I can also be used for the production of pharmaceutical compositions for male and female birth control (male birth control: DE-A 195 10 B62.0).
The compounds of general formula I with tissue-selective partial estrogenic action can be used primarily for prophylaxis and treatment of osteoporosis and for the production of preparations for substitution therapy in pre-, peri- and post-menopause (HRT=hormone replacement therapy) (Black; L. J.; Sato, M.; Rowley, E. R.; Magee, D. E.; Bekele, A.; Williams; D. C.; Cullinan, C. J.; Bendele, R.; Kauffman, R. F.; Bensch, W. R.; Frolik, C. A.; Termine, J. D. and Bryant, E. U.: Raloxifene [LY 139481 HCl] Prevents Bone Loss and Reduces Serum Cholesterol without Causing Uterine Hypertrophy in Ovariectomized Rats; J. Clin. Invest. 93: 63-69, 1994).
The invention also relates to pharmaceutical preparations that contain at least one compound of general formula I (or physiologically compatible addition salts with organic and inorganic acids of them) and the use of these compounds for the production of pharmaceutical agents, especially for treating estrogen-dependent diseases and tumors and pharmaceutical agents for hormone replacement therapy (HRT).
The compounds according to the invention and the acid addition salts are suitable for the production of pharmaceutical compositions and preparations. As active ingredients, the pharmaceutical compositions or pharmaceutical agents contain one or more of the compounds according to the invention or their acid addition salts, optionally mixed with other pharmacologically or pharmaceutically active substances. The production of the pharmaceutical agents is carried out in a known way, whereby the known and commonly used pharmaceutical adjuvants and other commonly used vehicles and diluents can be used.
As such vehicles and adjuvants, for example, those are suitable that are recommended or indicated in the following bibliographic references as adjuvants for pharmaceutics, cosmetics and related fields: Ullmans Encyklopxc3xa4die der technischen Chemie [Ullman""s Encyclopedia of Technical Chemistry], Volume 4 (1953), pages 1 to 39; Journal of Pharmaceutical Sciences, Volume 52 (1963), pages 91B and ff.; issued by Czetsch-Lindenwald, Hilfsstoffe fxc3xcr Pharmazie und angrenzende Gebiete [Adjuvants for Pharmaceutics and Related Fields]; Pharm. Ind. Issue 2, 1961, pages 72 and ff.; Dr. H. P. Fiedler, Lexikon der Hilfsstoffe fxc3xcr Pharmazie, Kosmetik und angrenzende Gebiete [Dictionary of Adjuvants for Pharmaceutics, Cosmetics and Related Fields] Cantor KG, Aulendorf in Wxc3xcrttemberg 1971.
The compounds can be administered orally or parenterally, for example intraperitoneally, intramuscularly, subcutaneously or percutaneously. The compounds can also be implanted in the tissue. The amount of the compounds to be administered varies within a wide range and can cover any effective amount. Based on the condition to be treated and the type of administration, the amount of the administered compound can be 0.1-25 mg/kg of body weight, preferably 0.5-5 mg/kg of body weight, per day. In humans, this corresponds to a daily dose of 5 to 1250 mg. The preferred daily dosage in humans is 50 to 200 mg. This is true especially for tumor therapy.
For oral administration, capsules, pills, tablets, coated tablets, etc., are suitable. In addition to the active ingredient, the dosage units can contain a pharmaceutically compatible vehicle, such as, for example, starch, sugar, sorbitol, gelatin, lubricant, silicic acid, talc, etc. The individual dosage units for oral administration can contain, for example, 5 to 500 mg of active ingredient.
To achieve better bio-availability of the active ingredient, the compounds can also be formulated as cyclodextrin clathrates. For this purpose, the compounds are reacted with xcex1-, xcex2- or xcex3-cyclodextrin or derivatives thereof (PCT/EP95/02656).
For parenteral administration, the active ingredients can be dissolved or suspended in a physiologically compatible diluent. As diluent, very frequently oils with or without the addition of a solubilizer, a surfactant, a suspending agent or emulsifier are used. Examples of oils that are used are olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil.
The compounds of general formula I can also be formulated in the form of a solution that is determined for oral administration and that in addition to the active compound of general formula I contains
a) a pharmaceutically compatible oil and/or
b) a pharmaceutically compatible lipophilic surfactant and/or
c) a pharmaceutically compatible hydrophilic surfactant and/or
d) a pharmaceutically compatible water-miscible solvent.
In this respect, reference is made in addition to WO 97/21440.
The compounds can also be used in the form of a depot injection or an implant preparation, which can be formulated in such a way that a delayed release of active ingredient is made possible.
As inert materials, implants can also contain, for example, biodegradable polymers or synthetic silicones such as, for example, silicone gum. In addition, the active ingredients can be embedded in, for example, a patch for percutaneous administration.
For the production of intravaginal systems (e.g., vaginal it rings) or intrauterine systems (e.g., pessaries, spirals) that are loaded with active compounds of general formula I, various polymers such as, for example, silicone polymers, ethylene vinyl, acetate, polyethylene or polypropylene are suitable.
The compounds according to the invention can be produced as described below. The examples below are used for a more detailed explanation of the invention. Other compounds of general formula I can be obtained by an analogous procedure using analogous reagents in the data contained in the examples.
Side chains R11 that do not contain any sulfur groups can be created analogously to the corresponding 7xcex1-position side chains of the compounds that are described in PCT/EP98/08470, whereby the 11xcex2-(5-chloropentyl)estra-1,3,5(10)-triene-3,17xcex2-diol that is described here in Example 1d or the 11xcex2-(5-iodopentyl)estra-1,3,5(10)-triene-3,17xcex2-diol that is described in Example 3a is now to be taken as a starting material.
A thio bridge in the side chain can be oxidized with sodium periodate to form sulfoxide; the sulfones are obtained from the sulfides with a peracid as an oxidizing agent, e.g., m-chloroperbenzoic acid.
The saponification of the ester groupings as well as esterification and etherification of free hydroxy groups is carried out in each case according to established processes of organic chemistry. By observing the varied reactivity of the esterified and free 3- and 17-hydroxy groups, the 3,17-diesters can be cleaved selectively in 3-position, and the 3-hydroxy-17-acyloxy compound can then be additionally functionalized specifically in the 3-position; it is equally possible to esterify or to etherify the 3,17-dihydroxy compound selectively only in the 3-position and then to introduce specifically another radical into the 17-position as already in the 3-position.
The acid addition salts of the compounds of general formula I can also be produced from the compounds of general formula I according to standard processes.